Many drugs are commonly employed in a granular form for preparing medical formulations, e.g. solid oral dosage forms. Beside the drug, the granules may comprise excipients such as surfactants, diluents, or disintegrating agents. Granules containing active pharmaceutical ingredients (API) can be coated subsequent to the granulation. By careful choice of the coating it is possible to control how fast and in what part of the digestive system the drug is released. In addition to the coating, controlling the physical characteristics of granules, such as size, roughness, morphology and porosity, is important as these parameters at least partly determine the amount of coating to be used.
Several approaches exist to produce granules of desired properties. These approaches generally involve an initial step of manufacturing granules followed by a unit operation aimed at sorting the produced granules according to size, in order to obtain only those granules within a required size range. Granulates can be produced by either building up particles from an initial seed or by breaking down a larger material into smaller sized particles. Often, cylinder-shaped granules are subjected to a spheronisation process, which produces spherically shaped particles, i.e. particles which for instance roll randomly as there is not or no longer just a single axis around which the particle can roll. A non-spheronised cylinder-shaped granule is characterised by the presence of a single axis around which the granule can roll. In the art, spheronised granules may also be referred to as pelletised granules or pellets. Dedicated apparatuses exist for spheronising or pelletising granules.
Typical operations employed in sorting the granules (spheronised or not) are fluidised beds or various types of sieves. However, the currently utilised procedures suffer from a number of weaknesses as will be discussed below.
WO2001/03089 describes devices for sorting pharmaceutical particles based on fluidisation principles. The housing chambers employed in these devices are equipped with rotating filters intended to retain particles larger than a desired minimum while the rotation of the filter portions will prevent clogging of the filter with (undesired) fine particles unavoidably formed during the preparation process. Application of fluidised beds for separation of particles is mainly useful for separating particles with aspect ratios close to 1, as the particles will tend to align with the fluidising stream in a way to minimise friction, i.e. longer particles can generally not be effectively separated from shorter particles with comparable widths.
US2004/0033266 discloses methods to obtain pharmaceutical particles of so-called monomodal size distributions. This is achieved by ultrasonicating large agglomerated particles resting on a screen with a mesh aperture size defining the intended particle size. The ultrasonication will break down the agglomerates into smaller particles which will then pass through the apertures and be collected on another screen with smaller holes. The methods are optimally suited for crystal agglomerates, which are held together by electrostatic interactions. The methods are much less suited for more complex types of particles or granulates, or those with aspect ratios significantly different from 1.
US2005/0269433 discloses integrated processes for producing granules from dry powders. Granulates produced in an early step of the process are milled and sorted in an intermediate, semi-dry state which is advantageous when the intermediate is size separated using screens or sieves. However, size separation through sieves has a problem similar to that of fluidised beds: particles can pass through the holes if their smallest dimensions are below those of the holes, and all but very long particles will eventually pass through the sieve. Accordingly, sieving methods fail to discriminate moderate to high-aspect-ratio particles from low-aspect-ratio particles.
Some previous methods for production of drug-containing granules, such as those described in application WO2003/032952, rely on the extrusion of a wet mass containing the drug and a suitable binder through a screen with a desired size of holes followed by drying and milling to produce a granulate. Separation according to size is then typically performed using sieves. The sieves are arranged to mechanically vibrate to enhance the probability that long granules will pass the sieve whilst moving through the sieve in their length direction. The sieved granulates in this class of process are as a consequence thereof generally observed to possess a relatively wide granule length distribution. Such a phenomenon is due to the above-noted characteristics of sieving methods. These distributions are nevertheless generally regarded as an acceptable limitation by those skilled in the art. As the sieve cannot discriminate on the basis of the lengths of the granules, it follows that the distributions are effectively width distributions. This has for a long period of time not been recognized in this field.